Family context and adoption of risky lifestyles: a study of English adolescents

This chapter presents the results of our empirical analysis using the recent data from the Longitudinal Survey of Young People in England (LSYPE), which is a panel study of young people aged between 13 and 14 in 2004 that is annually repeated. We develop an economic-theoretical framework with applied health econometric methods and use binary regression models to explain the probability of reporting a risky form of lifestyle at age 18 to 19. We consider seven risky forms of lifestyles, namely early sexual intercourse, teenage parenthood, early smoking, alcohol use, frequency of getting drunk, cannabis smoking and drug use. We undertake a hierarchical explanatory analysis where we include a larger vector of independent variables at each of the three steps of the analysis. This multi-step analysis enables us to understand the underlying mechanisms of the influence of family structure, especially lone-parent family, on the likelihood of adopting a range of unhealthy lifestyles in adolescence and whether family structure has a direct effect on those lifestyles, or an indirect effect, through its influence on other adolescents’ social characteristics

Facile access to a heterocyclic, sp3-rich chemical scaffold via a tandem condensation/intramolecular nitrone–alkene [3+2] cycloaddition strategy

A heterocyclic, sp3-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone–alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced

Long-term effect of teenage birth on earnings: Evidence from a British cohort study

We use data from the 1970 British Cohort Study and evaluate the effect of teenage motherhood on hourly earnings at age 30, 34, 38, and 42 using alternative non-experimental estimation methods including linear regression, matching methods, and Heckman sample selection models. We conclude that teenage motherhood has a significant negative long-term effect on hourly wages. At age 42, teenage mothers earn 12% less than other women and 29% less than women who have not had any children. When compared to non-teenage mothers, the pay penalty reduces over time and becomes insignificant on the long term

Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5‑HT_2C over 5‑HT_2B

Agonism of the 5-HT_2C serotonin receptor has been associated with the treatment of a number of diseases including obesity, psychiatric disorders, sexual health, and urology. However, the development of effective 5-HT_2C agonists has been hampered by the difficulty in obtaining selectivity over the closely related 5-HT_2B receptor, agonism of which is associated with irreversible cardiac valvulopathy. Understanding how to design selective agonists requires exploration of the structural features governing the functional uniqueness of the target receptor relative to related off targets. X-ray crystallography, the major experimental source of structural information, is a slow and challenging process for integral membrane proteins, and so is currently not feasible for every GPCR or GPCR–ligand complex. Therefore, the integration of existing ligand SAR data with GPCR modeling can be a practical alternative to provide this essential structural insight. To demonstrate this, we integrated SAR data from 39 azepine series 5-HT_2C agonists, comprising both selective and unselective examples, with our hierarchical GPCR modeling protocol (HGMP). Through this work we have been able to demonstrate how relatively small differences in the amino acid sequences of GPCRs can lead to significant differences in secondary structure and function, as supported by experimental data. In particular, this study suggests that conformational differences in the tilt of TM7 between 5-HT_2B and 5-HT_2C, which result from differences in interhelical interactions, may be the major source of selectivity in G-protein activation between these two receptors. Our approach also demonstrates how the use of GPCR models in conjunction with SAR data can be used to explain activity cliffs

The SAMPL6 SAMPLing challenge:assessing the reliability and efficiency of binding free energy calculations

Approaches for computing small molecule binding free energies based on molecular simulations are now regularly being employed by academic and industry practitioners to study receptor-ligand systems and prioritize the synthesis of small molecules for ligand design. Given the variety of methods and implementations available, it is natural to ask how the convergence rates and final predictions of these methods compare. In this study, we describe the concept and results for the SAMPL6 SAMPLing challenge, the first challenge from the SAMPL series focusing on the assessment of convergence properties and reproducibility of binding free energy methodologies. We provided parameter files, partial charges, and multiple initial geometries for two octa-acid (OA) and one cucurbit[8]uril (CB8) host-guest systems. Participants submitted binding free energy predictions as a function of the number of force and energy evaluations for seven different alchemical and physical-pathway (i.e., potential of mean force and weighted ensemble of trajectories) methodologies implemented with the GROMACS, AMBER, NAMD, or OpenMM simulation engines. To rank the methods, we developed an efficiency statistic based on bias and variance of the free energy estimates. For the two small OA binders, the free energy estimates computed with alchemical and potential of mean force approaches show relatively similar variance and bias as a function of the number of energy/force evaluations, with the attach-pull-release (APR), GROMACS expanded ensemble, and NAMD double decoupling submissions obtaining the greatest efficiency. The differences between the methods increase when analyzing the CB8-quinine system, where both the guest size and correlation times for system dynamics are greater. For this system, nonequilibrium switching (GROMACS/NS-DS/SB) obtained the overall highest efficiency. Surprisingly, the results suggest that specifying force field parameters and partial charges is insufficient to generally ensure reproducibility, and we observe differences between seemingly converged predictions ranging approximately from 0.3 to 1.0 kcal/mol, even with almost identical simulations parameters and system setup (e.g., Lennard-Jones cutoff, ionic composition). Further work will be required to completely identify the exact source of these discrepancies. Among the conclusions emerging from the data, we found that Hamiltonian replica exchange-while displaying very small variance-can be affected by a slowly-decaying bias that depends on the initial population of the replicas, that bidirectional estimators are significantly more efficient than unidirectional estimators for nonequilibrium free energy calculations for systems considered, and that the Berendsen barostat introduces non-negligible artifacts in expanded ensemble simulations